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Pulmonary Vascular Tone (pulmonary + vascular_tone)

Distribution by Scientific Domains

Medical Sciences	85%

Selected Abstracts

The Role of K+ Channels in Determining Pulmonary Vascular Tone, Oxygen Sensing, Cell Proliferation, and Apoptosis: Implications in Hypoxic Pulmonary Vasoconstriction and Pulmonary Arterial Hypertension

MICROCIRCULATION, Issue 8 2006
ROHIT MOUDGIL
ABSTRACT Potassium channels are tetrameric, membrane-spanning proteins that selectively conduct K+ at near diffusion-limited rates. Their remarkable ionic selectivity results from a highly-conserved K+ recognition sequence in the pore. The classical function of K+ channels is regulation of membrane potential (EM) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K+ egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a EM of about ,60 mV. It has been recently discovered that K+ channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage-gated (Kv), inward rectifier (Kir), calcium-sensitive (KCa), and two-pore (K2P) channels. Certain K+ channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen-sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits Kv1.5, which depolarizes EM, opens voltage-sensitive, L-type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia-inhibited K+ currents are not seen in systemic arterial SMCs. Kv expression is also transcriptionally regulated by HIF-1, and NFAT. Loss of PASMC Kv1.5 and Kv2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K+, thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring Kv expression (via Kv1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kv current (including an oxygen-sensitive component), whereas conduit PASMC current is a Kv/KCa mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K+ channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH. [source]

Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance

EXPERIMENTAL PHYSIOLOGY, Issue 2 2010
Philip N. Ainslie
Respiratory-induced changes in the partial pressures of arterial carbon dioxide and oxygen play a major role in cerebral blood flow (CBF) regulation. Elevations in (hypercapnia) lead to vasodilatation and increases in CBF, whereas reductions in (hypocapnia) lead to vasoconstriction and decreases in CBF. A fall in (hypoxia) below a certain threshold (<40,45 mmHg) also produces cerebral vasodilatation. Upon initial exposure to hypoxia, CBF is elevated via a greater relative degree of hypoxia compared with hypocapnia. At this point, hypoxia-induced elevations in blood pressure and loss of cerebral autoregulation, stimulation of neuronal pathways, angiogenesis, release of adenosine, endothelium-derived NO and a variety of autocoids and cytokines are additional factors acting to increase CBF. Following 2,3 days, however, the process of ventilatory acclimatization results in a progressive rise in ventilation, which increases and reduces , collectively acting to attenuate the initial rise in CBF. Other factors acting to lower CBF include elevations in haematocrit, sympathetic nerve activity and local and endothelium-derived vasoconstrictors. Hypoxia-induced alterations of cerebrovascular reactivity, autoregulation and pulmonary vascular tone may also affect CBF. Thus, the extent of change in CBF during exposure to hypoxia is dependent on the balance between the myriad of vasodilators and constrictors derived from the endothelium, neuronal innervations and perfusion pressure. This review examines the extent and mechanisms by which hypoxia regulates CBF. Particular focus will be given to the marked influence of hypoxia associated with exposure to high altitude and chronic lung disease. The associated implications of these hypoxia-induced integrative alterations for the regulation of CBF are discussed, and future avenues for research are proposed. [source]

The Role of K+ Channels in Determining Pulmonary Vascular Tone, Oxygen Sensing, Cell Proliferation, and Apoptosis: Implications in Hypoxic Pulmonary Vasoconstriction and Pulmonary Arterial Hypertension

Neuronal nitric oxide synthase does not contribute to the modulation of pulmonary vascular tone in fetal lambs with congenital diaphragmatic hernia (nNOS in CDH lambs),

PEDIATRIC PULMONOLOGY, Issue 4 2008
Anthony S. de Buys Roessingh MD
Abstract Aim The aim of this study was to determine the presence of the neuronal nitric oxide synthase (nNOS) in near full-term lambs with congenital diaphragmatic hernia (CDH) and its role in the modulation of pulmonary vascular basal tone. Methods We surgically created diaphragmatic hernia on the 85th day of gestation. On the 135th, catheters were used to measure pulmonary pressure and blood flow. We tested the effects of 7-nitroindazole (7-NINA), a specific nNOS antagonist and of N -nitro- l -arginine (l -NNA), a nonspecific nitric oxide synthase antagonist. In vitro, we tested the effects of the same drugs on isolated pulmonary vessels. The presence of nNOS protein in the lungs was detected by Western blot analysis. Results Neither 7-NINA nor l -NNA modified pulmonary vascular basal tone in vivo. After l -NNA injection, acetylcholine (ACh) did not decrease significantly pulmonary vascular resistance (PVR). In vitro, l -NNA increased the cholinergic contractile-response elicited by electric field stimulation (EFS) of vascular rings from lambs with diaphragmatic hernia. Conclusion We conclude that nNOS protein is present in the lungs and pulmonary artery of near full-term lamb fetuses with diaphragmatic hernia, but that it does not contribute to the reduction of pulmonary vascular tone at birth. Pediatr Pulmonol. 2008; 43:313,321. © 2008 Wiley-Liss, Inc. [source]

Blunted effect of the Kv channel inhibitor on pulmonary circulation in Tibetan sheep: A model for studying hypoxia and pulmonary artery pressure regulation

RESPIROLOGY, Issue 1 2004
Takeshi Ishizaki
Objective: The aim of this study was to assess the effect of 4-aminopyridine, a Kv channel inhibitor, on the pulmonary circulation of Tibetan sheep. It has been reported that chronic hypoxia downregulates the 4-aminopyridine (4AP)-sensitive Kv channel (which governs the membrane potential (Em) of pulmonary vascular smooth muscle cells in pulmonary vessels) without a change in 4AP sensitivity. Methodology: Pulmonary haemodynamic indices and blood gas analyses were measured in six young male animals in an altitude chamber that was adjusted to simulated altitudes of 0 m, 2260 m, and 4500 m. Drip infusion of 4AP, 10 mg/h for 3 h, was started and continued during the study. Results: With the increase in altitude mean pulmonary artery pressure increased and mean Pao2 decreased. 4AP had no effect on the levels of mean PPA, mean pulmonary artery wedge pressure, cardiac output, and mean PaO2, mean PaCO2, and mean pH at any altitude but tended to alter heart rate and mean arterial pressure at altitudes of 2260 m and 4500 m. Conclusion: It is concluded that the 4AP-sensitive Kv channel does not play a role in pulmonary vascular tone in high-altitude active Tibetan sheep. Their pulmonary vascular oxygen sensing appears not to involve Kv channels. [source]

Mechanisms involved in the regulation of bovine pulmonary vascular tone by the 5-HT1B receptor

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010
C McKenzie
Background and purpose:, 5-HT1B receptors may have a role in pulmonary hypertension. Their relationship with the activity of BKCa, a T-type voltage-operated calcium channel (VOCC) and cyclic nucleotide-mediated relaxation was examined. Experimental approach:, Ring segments of bovine pulmonary arteries were mounted in organ baths in modified Krebs,Henseleit buffer (37oC) under a tension of 20 mN and gassed with 95% O2/5% CO2. Isometric recordings were made using Chart 5 software. Key results:, Contractile responses to 5-HT (10 nM,300 µM) were inhibited similarly by the 5-HT1B receptor antagonist SB216641 (100 nM) and the T-type VOCC blockers mibefradil (10 µM) and NNC550396 (10 µM) with no additive effect between SB216641 and mibefradil. Inhibition by SB216641 was prevented by the potassium channel blocker, charybdotoxin (100 nM). 5-HT1B receptor activation and charybdotoxin produced a mibefradil-sensitive potentiation of responses to U46619. Bradykinin (0.1 nM,30 µM), sodium nitroprusside (0.01 nM,3 µM), zaprinast (1 nM,3 µM), isoprenaline (0.1 nM,10 µM) and rolipram (1 nM,3 µM) produced 50% relaxation of arteries constricted with 5-HT (1,3 µM) or U46619 (30,50 nM) in the presence of 5-HT1B receptor activation, but full relaxation of arteries constricted with U46619, the 5-HT2A receptor agonist 2,5 dimethoxy-4 iodoamphetamine (1 µM) or 5-HT in the presence of 5-HT1B receptor antagonism. Enhanced relaxation of 5-HT-constricted arteries by cGMP-dependent pathways, seen in the presence of the 5-HT1B receptor antagonist, was reversed by charybdotoxin whereas cAMP-dependent relaxation was only partly reversed by charybdotoxin. Conclusions and implications:, 5-HT1B receptors couple to inhibition of BKCa, thus increasing tissue sensitivity to contractile agonists by activating a T-type VOCC and impairing cGMP-mediated relaxation. Impaired cAMP-mediated relaxation was only partly mediated by inhibition of BKCa. [source]